Exercise Blunts Insulin Resistance & Hyperlipidaemia Due to 7-Day +50% / +75% Overfeeding in Athletic Young Men

Gluttony is one of the 7 sins - no wonder that eating more than you "deserve" makes you ugly and sick.

Everybody knows that "physical activity is good for you". Some, like me, even go so far to say that it's necessary - at least for those of us who plan to lead a healthy life into their old age. The classic idea that many of its beneficial effects are related to the ability of physical exercise to fix your dietary lapses on the other hand, has turned out to be - at best - part of of the 'health equation' (see "The Fallacy of Working Out to Burn Energy" | read more).

Nevertheless, Jean-Phillipe Walhin and his colleagues from the University of Bath demonstrate in their most recent paper that the ability of exercise to blunt the ill health effects of short-term overfeeding is a non-negligible part of the 'health equation'.

Don't worry this is a human trial!

For their experiment Jean-Philippe Walhin, Judith D. Richardson, James A. Betts, and Dylan Thompson recruited healthy, "habitually active" male volunteers aged 25 ± 7 years. Eligible were only men who participating in structured vigorous-intensity exercise for thirty minutes or more, at least three times per week. After 26 athletic young men who met these criteria were found, they were randomized to one out of two groups by a third party and put on ...

• a fixed energy surplus for 7 days on which their physical activity was restricted (SUR), or
• the same energy surplus and general activity limit, but w/ daily cardio training (SUR+EX). 

The target increase in energy intake for both groups was 50%. Both groups also reduced their general daily activity to ≤4000 steps. Contrary to the SUR group, for which the 4,000 steps / day was all they got in terms of 'exercise', the SUR+EX group had to perform a daily bout of 'vigorous-intensity' treadmill running (5 min warm-up at 60 % V O2maxthen 45 min at 70 % V O2max). To ensure compliance, all subjects had to wear a pedometer (Yamax, Japan).

The energy expenditure was compensated!

As a regular here at the SuppVersity you will be aware that this study would hardly have made it into the SuppVersity articles, if that, i.e. one group eats + 50% and sits around all day, while the other consumes the same amount of energy and works out, would be all the experiment had to offer. What makes the paper actually interesting is something the scientists marked as "critically" in the abstract to their paper:

"[T]he SUR+EX group received additional dietary energy intake to account for the energy expended during exercise; thus maintaining a matched energy surplus." (my emphasis in Walhin. 2013)

Practically speaking this meant that the subjects in the SUR + EX group had to eat even more food to achieve an additional +25% increase in energy intake that was meant to compensate for the extra energy the subjects in this group would be burning during their daily exercise sessions.

Q: How did the scientists know that +25% was the correct number? A: They calculated it: EPOC (6.6% of the energy expended during the run) + diet induced thermogenesis (10%) - energy that would have been expended when the subjects rested = approx. 25% of the baseline intake.

If we take the 'energy bonus' of +25% into account, we are thus dealing with a comparison of a +50% energy intake diet without exercise and a +75% energy intake diet with exercise. Whether or not this would yield a "matched energy surplus" is something I personally don't care about.

Why? Well, outside of a metabolic ward you got to rely on a bunch of funky equations and the hilariously stupid assumption that energy intake and energy expenditure would not depend on each other. Against that background, it does not really matter that the data in Figure 1 indicates that the energy surpluses ended up being ca. 18% apart. In view of the unreliability of these kinds of  'energy in vs. energy out' calculations, this is still close enough to qualify the energy surplus as being roughly identical.

Figure 1: Total energy intake and calculated energy surplus (in kcal/day) in the SAR vs. SAR+EX groups (Walhin. 2013)

To assess the effects of this protocol, fasted blood samples and abdominal subcutaneous adipose tissue biopsies were obtained and oral glucose tolerance tests conducted at baseline and during a follow up visit to the laboratory one week later. Instead of reiterating the verbose summary of the corresponding findings, I have compiled a comprehensive overview of the most significant (not necessarily statistically, by the way) study outcomes in Figure 2:

Figure 2: Relative changes (% of baseline) in glucose + fat metabolism, adiponectin, leptin and alanine transaminase levels (the latter a considered a measure of liver strain) during one week of overfeeding (Walhin. 2013)

As you may guess based on the relative changes to the parameters of glucose management (see Figure 2, left), the insulinaemic responses to a standardized glucose load increased 2-fold from baseline to follow-up in the SUR group (Δ17 ± 16 nmol/120min; P=0.002). In the SUR+EX group, on the other hand, the single week of (even more pronounced) gluttony did not lead to comparable increases in insulin resistance or glucose intolerance (SUR+EX group → Δ1 ±6 nmol/120min).

Not shown in Figure 2 are the results of the gene essays the scientists conducted. Unsurprisingly, the results are not significantly different. It's once more the "lazy" SUR group, in whom the gene expression in the fat (=adipose) tissue turned from 'neutral' to 'pro-diabetic and -dyslipidaemic:

"Seven of 17 genes within adipose tissue were differentially-expressed in the SUR group; expression of SREBP1c, FAS and GLUT4 was significantly up-regulated and expression of PDK4, IRS2, HSL and VISFATIN was significantly down-regulated (P≤0.05)." (Walhin. 2013)

It is thus no wonder that AMPK, one of the most important markers we have, when we are talking about issues with blood glucose management (learn more), or, even more specifically, the ratio of phosphorylated to unphosphorylated protein was also significantly down-regulated elusively in the SUR group (P=0.005).

"Bulking Done Right: +1,000 Kcal/day Overfeeding, Fitness, Fatness, Hormones & More" | more

Here you have it! In the short term  you can 'out-exercise' a miserable diet, but I warn you. While daily cardio or other forms of training may ameliorate many of the negative health effects of overfeeding in the short run, the weight gain that comes whenever you eat almost twice as much food as you would need will take its toll, though - if not sooner, then later.

In the long-run, the 'run' we are all in, your health and physique are thus going to depend on your ability to control your energy intake, and not on your adherence to a given exercise program. In the short run, and during a strategic bulk (e.g. to build muscle), your workouts will provide a certain degree of protection from the most immediate detrimental health effects of the gluttony the vast majority of our fellow 'Westerners' is indulging in.

References:

• Walhin JP, Richardson JD, Betts JA, Thompson D. Exercise counteracts the effects of short-term overfeeding and reduced physical activity independent of energy imbalance in healthy young men. J Physiol. 2013 Oct 28.

Gene-ial or Dan-Gene-rous? Better Make Sure You Are Made For Every Other Day Fasting, If You Don't Want to Ruin Your Glucose + Lipid Metabolism and Become Viscerally Obese

Yes! I freely admit that I do have a problem with the subliminal "binge and starve" of the popular every other day fast, because it paves the not so royal road to binge eating disorders.

Only 2 years ago, there was hardly anyone but the followers of Martin Berkhan's "Lean Gains" regimen who knew what intermittent fasting would be. Ironically, now that mainstream is catching on, the hype within the fitness community is slowly abating  - maybe part of the reason is that it's no longer "cool" enough now that your fat neighbor does it ;-).

It goes without saying that the mainstream version comes without an obligatory exercise component and - what's probably even worse - in the absence of macronutrient, let alone food prescriptions that would make sure that the every other day fasts that are becoming increasingly popular these days become "binge and starve" protocols.

The every other day fast, a gateway to eating disorders?

I could probably write a whole article about the potential of feast and fast strategies to function as a gateway to binge-eating disorders, but I know that most of you will discard that by stating: "Pah, that's happening only to the psychologically labile person who can't control his-/herself"... I will argue against that in another article, but I want to let you know here and now, that you could hardly be more off.

Did you know that eggs can improve the lipid profile of most of us?

Stay calm! In view of the fact that rodents in the wild-type control group, who had fully functional LDL receptors did not show a similar negative response to the well-meant dietary intervention, the results of the study at hand are hopefully irrelevant for most of you. If you do have friends and relatives with inexplicably high cholesterol levels, you would however be ill-advised to encourage them to battle their problems with every other day fasting.

Anyway... What this article is actually about is a paper from the British Journal of Nutrition. It was written by Dorighello et al. and has been published online ahead of print. The corresponding study was designed to test the hypothesis that alternate day fasting, which has previously been shown ... 

• to decrease established metabolic risk factors of CVD and diabetes in human subjects and rodents (Varady. 2007),
• to reduce the production of liver mitochondrial reactive oxygen in mice (Caro. 2008), and 
• to increases the lifespan of rodents (Martin. 2006)

would ameliorate tissue mitochondrial oxidative stress and glucose intolerancr in LDL-receptor knockout mice. The LDL-receptor negative mouse is a common, or rather the scientific model of familial high cholesterol (these are the people who are put on a statin the very moment, they enter their doctor's office).

What the scientists expected and what they found were two pair of shoes

I guess you don't have to be a rocket scientists to see what the data in Figure 1 is telling us: In spite of a 20% reduction in energy intake (over the whole week), the rodents in the Dorighello study did not benefit from their every other day fasting regimen (EODF)

Figure 1: Changes in lipid and blood glucose levels (relative to control on ad libitum diet; left) and carcass composition in % of total weight (right; data based on Dorighello. 2013)

Accordingly, the Brazilian scientists who had expected that the fasting induced energy restriction, (-20%), alone, should ameliorate the metabolic disturbances in LDL-receptor knockout mice, and reduce their susceptibility to atherosclerosis, had to acknowledge that their clever every other day fasting regimen can have unexpected and, in the last consequence, eventually fatal effects on the heart health of the laboratory mice:

• Epididymal and carcass fat depots and adipocyte size were significantly enlarged by 15, 72 and 68 %, respectively.
• Pasma levels of leptin were 50 % higher in the EODF mice than in the ad libitum-fed mice.
• EODF mice showed increased plasma levels of cholesterol -  total cholesterol (37 %), VLDL-cholesterol (195 %) and LDL-cholesterol (50 %). 
• The glucose homeostasis of the "EODF mice" also disturbed. The scientists observed a +40 % increase in glycemia and a +50% increase in insulinaemia. In short, the mice became glucose intolerant and insulin resistant.
• The significant increases in systemic inflammatory markers, TNF-a and C-reactive protein, only topped the list of negative side effects of the every other day fast off.

Overall this lead to a 3-fold increase in spontaneous atherosclerosis development, an effect of which it cannot be said often enough that it was observed exclusively in the LDL-receptor negative mice.

Practically speaking... In spite of the fact that the main take home message of the study at hand may be relevant only for those who harbor a certain genetic disposition, I do not recommend a zero calorie every other day fast to anyone - irrespective of whether he or she does or doesn't have LDL receptors  ;-)

If you are not aware of cases of familiar hyper-cholesteraemia and want to improve your lipid metabolism by fasting and eating clean, I suggest you re-read my previous article about the "Two Day High-Protein, Low-Carb Fast" and try this, or a classic intermittent fasting routine with a 6-8h feeding window to shed some body fat and get in better metabolic shape.

So what does this mean? The results of the study at hand are exemplary of something regular SuppVersity readers have encountered a dozen of times, already. A fact that vindicates the often-heard, but rarely understood notion that "we are all different". As the study at  hand clearly shows, our gene's and their consequences on our physiology determine not just what we should eat, but also when we shoult eat it. 

You got to be wary, though! Contrary to what you may read in some shiny magazines and on banners on the Internet, the often advertized "gene type diet" is not even on the horizon, yet.

Yes, we can (theoretically) identify each and every gene in our bodies, but in contrast to a general LDL receptor dysfunction, many of the more subtle genetic differences are as of yet totally unknown. Any list of foods, or, as this study shows, suggest food frequency rules you may get are up to know about as accurate as the names of the man or woman of your dreams you will get if you follow the friendly advice the music television advertisement gives you and "send an SMS with the keyword 'love' and your name" to a random number. Even for the well-studied APO-E polymorphisms, scientists are time and again surprised to find that their results are not in line with data from previous studies. Contemporary accepted implications, such as "people whose apolipoproteins belong to the APO-E4 class will do more harm than good if they consume larg(er) amounts of fish oil" could thus be as flawed as the idea that only fat can make you fat - likewise the result of premature conclusions that seemed logical in view of the contemporarily available, highly insufficient data, by the way.

References:

• Caro P, Gómez J, López-Torres M, Sánchez I, Naudi A, Portero-Otín M, Pamplona R, Barja G. Effect of every other day feeding on mitochondrial free radical production and oxidative stress in mouse liver. Rejuvenation Res. 2008 Jun;11(3):621-9.
• Martin B, Mattson MP, Maudsley S. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev. 2006 Aug;5(3):332-53.
• Varady KA, Hellerstein MK. Alternate-day fasting and chronic disease prevention: a review of human and animal trials. Am J Clin Nutr. 2007 Jul;86(1):7-13. Review.

4g of Conjugated Linoleic Acid Promote CYP17A1 + Leydig Cell Testosterone Production and Increase Cardio-Mediated Muscle, Strength and Endurance Gains

"That's all the exercise in induced T-response, bro. Now shut up, I got to squat!"

Yes, this is another of those rodent studies of which we simply don't know if the results will eventually translate to humans. In contrast to previous studies on CLA, which dealt with weight loss and produced marvelous results (see "CLA Destroys Body Fat & Increases Endurance!" | read more) which could not be reproduced in human trials.

This very recent paper from Italy deals with CLA's effects on exercise, testosterone, and potential gains in muscle mass and leaves the parameter body fat out of the equation (Barone. 2013).

"Hold on, that's not news, is it?"

When Roy Nelson shot me the link to the pertinent paper by Rosario Barone et al. (2013), the above, i.e. "Hold on, that's not news, is it?" was actually my first thought. After all, I had written about the purported muscle building effects of CLA in the past (see "Review Claims: CLA & Fish Oil Improve "Anabolic" Effects of Exercise - What Does the SuppVersity Sniff Test Say?" | read more). After briefly checking my previous article, I did realize, though: This is news!

The previous article did not discuss the same results. It did however come from the same team of Italian researches and made the claim that CLA & fish oil would be natural anabolics (read it!) - a claim I reviewed and wrote:

"[...] as far as ergogenic and/or anabolic effects are concerned, CLA is unquestionably the more promising fatty acid off the "two" (actually we are talking about four fatty acids, here: DHA + EPA = fish oil and cis-9,trans-11 and trans-10,cis-12 CLA)." (SuppVersity. 2013)

I have to admit, though, that I was thinking of CLA's ability to block the storage of body fat on a bulk, primarily - not so much about its not yet fully, but at least half-way established effects on exercise performance. The testosterone boosting effects, on the other hand, were something I discarded, so that it's about time to look at them more closely.

In vitro + in vivo - that's the way Barone et al. did it

In a first attempt to access the effects of CLA on the testicular androgen production, the scientists from the University and Hospital of Palermo conducted a couple of tests in the petri dish. Usually boring stuff, if it were not for geeks like me (and some of you) who always ask the nasty question: "Why".

Figure 1: The same research group published a paper that showed increased testosterone in young men on a resistance training regimen. It is therefore not totally unlikely that the results do translate to human beings; the figure shows the total testosterone before vs. after a workout in ng/dl (Macaluso. 2012)

In this case, we are lucky, because Barone et al. did not focus solely on the amount of steroids the the leydig tumour cells (don't worry that should work with regular cells, as well) were spilling out. They also tested for enzymatic changes and observed that as 17α-hydroxylase/17,20-lyase (CYP17A1), which converts progesterone into androstenedione and has  been demonstrated to have direct downstream effects on the testosterone production (Svechnikov. 2009; Weisser. 2011).

As every SuppVersity reader knows, the cytochrome P450 enzyme cascade is on of the most powerful and overlooked actors in the steroid orchestrate. While CYP17A1, which does effectively increase the production of testosterone pre-cursors and will thus exert an indirect beneficial effect on the testosterone production, other members of the cytochrome family facilitate the conversion and clearance of testosterone.

Against that background it was sound to expect to observe similar effects in the in-vivo part of the study. The interplay with other enzymes, however, could easily have thwarted the results. Outside of the petri dish the sheer number of variables that could change the outcome of the study makes it more or less impossible to predict the "exact" study outcome and - I want to emphasize this - the latter could well look slightly or completely different from what you see in Figure 2, when you went ahead and tried to support your training efforts with 4g of the patented Tonalin® FFA 80:

Figure 2: Free testosterone and CYP17A1 expression in the supplemented (CLA-) /  unsupplemented (PLA-) mice after 6 weeks of no (SED) or 15-60min (ramp up) of exercise 5x per week (Barone. 2013).

I hope you did notice the important hint I hid in the last sentence above Figure 2, where it says: "Support your training efforts..." If you didn't take a look at Figure 2 ... I guess, it's obvious to see that this short insert is of paramount importance: No training, no CLA bonus!

"The protein expression of CYP17A1 was significantly higher in both the trained groups (PLA-TR and CLA-TR) compared to the sedentary groups (PLA-SED and CLA-SED) (P <0.01). Moreover, CLA supplementation induced a further increase in CYP17A1 protein in the CLA-TR group compared to the PLA-TR group (P < 0.01)" (Barone. 2013)

In other words, training alone is a CYP17A1 powered testosterone booster and CLA is an adjuvant, which has no effect in the absence of 6 weeks with five "cardio" sessions/week at an ever-increasing pace and duration (15-60min and 3.2-4.8m/min from week 1-6).

Figure 4: Body weight gain, and force/body weight gain  (in %; top) and distance traveled relative to SED-PLA group (Barone. 2013)

"Wow that's exciting, isn't it?" Actually no - not really. The increase in testosterone alone would hardly be worth the paper this article is probably never going to be printed on. What is at least borderline exciting, though, are the increase in muscle gains, strength and running distance the rodents covered in a standardized test (see Figure 3).

Yeah, I have to admit: The data does look exciting, but that can be said of the previously referenced study by Macaluso, as well. The said human trial (see Figure 1), however, tells us that it's probably unrealistic to expect similarly pronounced effects with even more CLA (6g in the Macaluso study from 2012) in men.

Personally, I would save the money, but if you want to try it: Go ahead... and tell us if it works ;-)

I, for my part, am missing anecdotal evidence (You can't tell me that there is no one who has tried that already - so where are the "CLA is king, bro!" posts on the various boards?), the confirmation of this or at least similar effects by other scientists and a 'Conflict of Interest' declaration at the end of a paper that puts such an emphasis on the "®" in  Tonalin® FFA 80.

References:

• Barone, R, Macaluso F, Catanese P, Marino Gammazza A, Rizzuto L, et al. Endurance Exercise and Conjugated Linoleic Acid (CLA) Supplementation Up-Regulate CYP17A1 and Stimulate Testosterone Biosynthesis.  PLoS ONE 8(11): e79686.
• Macaluso F, Morici G, Catanese P, Ardizzone NM, Marino Gammazza A, Bonsignore G, Lo Giudice G, Stampone T, Barone R, Farina F, Di Felice V. Effect of conjugated linoleic acid on testosterone levels in vitro and in vivo after an acute bout of resistance exercise. J Strength Cond Res. 2012 Jun;26(6):1667-74.
• Svechnikov K, Spatafora C, Svechnikova I, Tringali C, Söder O. Effects of resveratrol analogs on steroidogenesis and mitochondrial function in rat Leydig cells in vitro. J Appl Toxicol. 2009 Nov;29(8):673-80.
• Weisser J, Landreh L, Söder O, Svechnikov K. Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells. Mol Cell Endocrinol. 2011 Jul 20;341(1-2):18-24. doi: 10.1016/j.mce.2011.03.008.

Theanine or Caffeine? Soda, Black or Green Tea? What's Going to Get Your Brain Going? Plus: What About Sleep?

Caffeinated soft drink, coffee or tea, caffeine alone or caffeine + l-theanine what's going to yield the desired afterburner effect for your brain? The answer to this question came out probably less straight forward than you'd expected.

"L-theanine, coffee or both? What's going to get your brain going?" That's the question form the title of today's SuppVersity article and it's a question with an astonishingly simple answer:  Both!

I guess you will be well aware that both caffeine and l-theanine have scientific evidence to support their usefulness as cognitive enhancers (Quinlan. 2000; Hindmarch. 2000; Nathan. 2006). Their interactions however have not been studied that extensively.

It's thus worth to take a closer look at the data Hira Zameer et al. collected for their most recent paper in the International Journal of Endorsing Health Science Research - data on the effects these agents can have on the cognitive performance and reaction times of 87 healthy young women (18-19 years), when they are consumed as part of hot and cold beverages (Zameer. 2013)

Compare to caffeine, which is literally on everyone's lips, only few people actually know what l-theanine is. Quite often you will see it being mislabled as the "the caffeine in tea" and that despite the fact that it is not even a methylxanthine, but (as the "L-" already suggests) an amino acid. Against that background it appears prudent to start today's SuppVersity article with a mini-summary of the the (astonishingly few) things we know about gamma-glutamylethylamide or 5-N-ethyl-glutamine, an amino acid and a glutamic acid analog that's - who would have guessed that - primarily found in tea.

L-theanine - the "tea caffeine"!?

L-theanine has gained quite some attention in the field of neuroscience. Kakuda et al., for example report significant neuroprotective effects in their 2002 paper. Protection is however not the only thing l-theanine can do for you. Previous studies have shown that it has direct beneficial effects on the activity of alpha frequency band (8–14 Hz), the cellular pacemaker of the human body (Kobayashi, 1998; Juneja, 1999).

Not to be confused: L-Theanine vs. theacrine as in "Theacrine Will Get You Going - Every Day! Camellia Kucha Alkaloid Acts via Dopamine and Adenosine" | more

In this context it's important to know that l-theanine has, in contrast to many other agents, the ability to cross the blood-brain barrier. It does so relatively easily, but not rapidly: Based on the current scientific evidence it takes ca. 30 minutes from the moment of its ingestion, before the first changes in neurotransmitter levels can be observed.

Structurally, L-theanine is similar to the excitatory neurotransmitter glutamic acid (Nathan. 2006). Consequently, L-theanine has the ability to antagonizes the central effects of glutamate by inhibiting glutamate reuptake and blockade of glutamate receptors in the hippocampus (Kakuda. 2002). This process goes hand in hand with an increased release of the "calming" neurotransmitter GABA and a concomitant decline norepinephrine levels.

In view of its GABA-ergic effects, it's not really surprising that L-theanine has also been found to ameliorate the blood pressure rising effects of caffeine and tone down the CNS responses (Eschenhauer. 2006) - quite a neat effect for an agent you get for free with your daily dose of caffeine in tea, isn't it?

Don't be fooled - tea will also mess with your sleep quality, but as data from an Y2K study by Hindmarch et al. shows, "day-long tea consumption produces similar alerting effects to coffee, despite lower caffeine levels, but is less likely to disrupt sleep." During the study (results see figure on the left), the drinks were administered on four occasions during the day (0900, 1300, 1700 and 2300 hours).

In subjects who had to perform a standardized series of stressful tasks, L-theanine has been shown to reduce the heart rate and salivary immunoglobulin A release via direct inhibition of the excitation of cortical neurons (Kimura. 2007). With the close connection between stress exposure, the activation of the sympathetic nervous system and the ensuing release of vasoconstricting hormones, it is not unlikely to assume that L-theanine's blood pressure lowering effects are a simple result of its ability to buffer the CNS activity and reduce the adrenergic tone (Kulkarni. 1998; Matthews. 2004).

Enough of the past, let's get to the most recent results

Now that you are in the know about some of the most prominent effects of l-theanine consumption, let's see how it fares in a direct comparison to everyone darling - caffeine!

Figure 1: Effects of soda, (black) tea and green tea ingestion on reaction time, concentration test performance, blood pressure and heart & pulse rate (Zemeer. 2013)

I already mentioned that the subjects, 87 young adult females (18-19 years of age) were randomly assigned to three groups

• Group A consumed a cold beverages in the form of soft drinks (caffeine only)
• Group B consumed a serving of black tea (caffeine + l-theanine)
• Group C consumed a serving of green tea (min. caffeine + l-theanine)

Before and 45 min after the beverage ingestion the scientists monitored the cardiovascular and neurophysiological responses. After the "immediately post" data had been collected, all participants engaged in a series of standardized reaction time and concentration tests that yielded astonishingly similar results:

• Both tea preparations "proved to be more sufficient in enhancing concentration and focusing power of the individuals by reducing the distractions during a task at hand" (Zemeer. 2013)
• The concentration levels during a passage reading task in the tea condition were likewise significantly higher (p < 0.05) than in the soft drink condition, which had only marginal effects on the subjects' ability to focus.

The analysis of the cardiovascular parameters, on the other hand, showed that all groups experienced a decline in systolic blood pressure, surprisingly,

Ever wondered about the "exact" pharmacology of caffeine? Tom Edwards captured it in 1990.

"[...] a significant reduction in systolic blood pressure by 13 and 19 mm Hg was evident amongst the candidates of group A and C who were assigned for the intake of soft drink (caffeine) and green tea (L-theanine), respectively (p < 0.05) as compared to individuals who were belonged to tea (caffeine + L theanine) consumption group. Similarly, a considerable decline in diastolic blood pressure by 12 mm Hg was more noticeable among the participants who were subjected to consume soft drink (caffeine) and green tea (L-theanine) (p < 0.05) as compared to the group B, tea consumers.

Physiological rise in the heart rate of the individuals was observed when their basal heart rates were taken before and after consumption of hot and cold beverages. But a less significant rise in heart rate by 1bpm was remarkable among group C (L-theanine) candidates (P=0.31). In contrast to heart rate, a significant increase in pulse rate by 10 bpm was reported within the members of group C, green tea (L-theanine) consumers (P=0.01). " (Zemeer. 2013)

If you look back at my brief summary of the current data on l-theanine in the upper part of this article, you will probably find the increase in blood pressure and the modulatory effects on the heart rate of the subjects odd - in the end, it is however perfect evidence that the effects of neurotransmitters and agents that can influence their levels and ratios are hard, if not impossible to predict. As with GABA (see "SuppVersity Science Round-Up: Paradoxical Effects of GABA. Plus: GABA-Alternatives" | read more) it may thus well be that tea really psyches you up and a "simple" coffee, where caffeine runs the whole show, is much better suited for you than a huge cup of black or green tea.

SuppVersity Suggested Read: "Green Tea Extracts for Building Strength & Size and Losing Weight - Fact or Fraud? Or, Why It is Always Worth Taking a Look at the Data that Is NOT in the Abstract. " | read more

So what do we make of these results, if the effects are so "difficult to predict"? Unlike the prediction the answer to this question is actually surprisingly straight forward, because all uncertainties aside, the study at hand did eventually confirm what most people know from their own experience: Tea, unlike coffee has a stimulatory, yet calming effect and is thus slightly more useful, whenever you are looking for focus and mental clarity.

If you want to tear down the gym, the rather aggressive and agitating effects of "unbuffered" (=no l-theanine around) of caffeine should be your first choice - unless, of course, the agitation turns into anxiety and instead of hammering away curl after curl you find yourself sitting on the bench shivering of negative excitement.

References:

• Eschenauer G, Sweet BV. Pharmacology and therapeutic uses of theanine. Am J Health Syst Pharm. 2006 Jan 1;63(1):26, 28-30.
• Hindmarch I, Rigney U, Stanley N, Quinlan P, Rycroft J, Lane J. A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality. Psychopharmacology (Berl). 2000 Apr;149(3):203-16.
• Nathan PJ, Lu K, Gray M, Oliver C. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006;6(2):21-30. 
• Kakuda T, Nozawa A, Sugimoto A, Niino H. Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors. Biosci Biotechnol Biochem. 2002 Dec;66(12):2683-6. 
• Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007 Jan;74(1):39-45.
• Kulkarni S, O'Farrell I, Erasi M, Kochar MS. Stress and hypertension. WMJ. 1998 Dec;97(11):34-8. Review.
• Kuriyama S, Shimazu T, Ohmori K, Kikuchi N, Nakaya N, Nishino Y, Tsubono Y, Tsuji I. Green tea consumption and mortality due to cardiovascular disease, cancer, and all causes in Japan: the Ohsaki study. JAMA. 2006 Sep 13;296(10):1255-65.
• Quinlan PT, Lane J, Moore KL, Aspen J, Rycroft JA, O'Brien DC. The acute physiological and mood effects of tea and coffee: the role of caffeine level. Pharmacol Biochem Behav. 2000 May;66(1):19-28.
• Zameer et a.. Comparative Effects Of Caffeine & L-Theanine Consumption On Subjective Cardiovascular Signs And Neurophysiological Responses. International journal of endorsing health science research. 2013; 1(1): 38-42.

The Healthy Taste of Olive Oil. Would the Flavor Be Enough to Induce At Least Some of Its Health & Satiety Effects? Plus: Cholesterol Control - Pomace vs. Refined Olive Oil

What about an EVOO perfume, then?

I know, it sounds crazy, but in view of what you've learned in previous articles here at the SuppVersity about sweet taste receptors (learn more) and their far-reaching influence on our metabolism, it does not appear to far-fetched to assume that there is a receptor that "tastes" the flavor-active compounds of olive oil that's responsible for some of its beneficial health effects - right?

I guess, Sabine Frank and almost a dozen of other scientists from Germany and Austria must have had a similar idea, when they came up with the research question of their most recent study.

Olive oil flavored yoghurt?! Really?

I suppose, olive oil flavored, or, more specifically, low-fat yogurt mixed with a fat-free aroma extract from olive oil may not sound appealing to the average Western customer, but it would certainly deserve the label "functional food":

Figure 1: Only the olive oil enhanced yogurt will also enhance the activity of the frontal operculum (Frank. 2013)

As you can see in Figure 1, it's a functional food that has a statistically highly significant effect on the cerebral blood flow in the frontal operculum 30 and 120 min after a meal: This and the increased activity in the anterior insula of which the scientists found that it correlated positively with the postprandial change in bloos glucose change in the 11 healthy male subjects of the study, clearly suggest: The taste of olive oil alone has significant effects on the blood flow in parts of the brain that are involved in the control of energy intake and metabolic rate.

"What is the "frontal opercular" and why would I care about its blood supply?"

If the subheading to this paragraphs describes what you are thinking right now, it's about time to take a look at the little information we have about the frontal operculum:

• 

  Suggested read: "Pimp My Olive Oil! When Virgin is not Phenol-Rich Enough: The Pharmacokinetics of Phenol-Enriched Virgin Olive Oil." | read more

  We know from previous studies that the frontal operculum (FP) is sensitive to food intake.
• The study at hand shows that the FP does not care about caloric values (the yogurts were isocaloric).
• In task-related studies, the frontal operculum as part of the primary taste cortex, has shown pronounced activation to visual food cues and anticipation of food intake.
• The activation of the frontal operculum appears to control the "this smells good" or "this looks good, I must have it" response that makes weight loss so difficult.
• There is a telling relation between the sensitivity of the frontal operculum and the BMI of a person (Batterink. 2010; Yokum. 2011)
• Earlier fMRI studies showed that oral delivery of a drop of fat leads to an immediate increase in insular and frontal opercular activity, which suggests that there are "fat taste receptors" somewhere in the oral cavity or digestive tract that are wired to the the frontal perculum (Small. 2012).

Now, in context of the results of the study at hand, it is obviously the last of these points, which is particularly interesting. The discovery Frank et al. made would after all suggest that we can get satisfactory "fat effect" without the fat - simply by having the right "aroma."

Figure 2: Modulating effect of the minor components of pomace olive oil (POMACE) on lipid composition in 10 healthy young men (Cabello-Moruno. 2013) - severs as illustration for the importance of the "non-fat" components for our health.

Frank et al. also point out that the fact that they measured the CBF not immediately but 30 min and 120 min after the consumption of the yogurt would make it quite unlikely that they had mistaken an acute aroma response for what they believe is the "association with fat" - in other words, the researchers believe that the ingestion of the olive oil flavor components "modifies later responses to achieve an appropriate sensory control." Effects just as we know them from glucose and artificial sweeteners which "prepare" the body to release insulin.

Per capita consumption of vegetable oils and fats in selected European countries in 2009 (Eurostat. 2011)

Bottom line: I guess it is too early to say, whether and what kind of applications the said olive oil extract could have in the future. What the study does however show is that focusing on macros and even micronutrients, only, is insufficient.

In fact, the "ideal" diet, with the perfect macros and 100% adherence could in the end turn out to produce inferior results to a "sub-optimal", but tasty diet with olive oil and other aromas triggering all-sorts of still to be elucidated beneficial downstream effects on our physiology and psychology.

Reference: 

• Batterink L, Yokum S, Stice E. Body mass correlates inversely with inhibitory control in response to food among adolescent girls: an fMRI study. Neuroimage 2010;52:1696–703.
• Cabello-Moruno R, Martinez-Force E, Montero E, Perona JS. Minor components of olive oil facilitate the triglyceride clearance from postprandial lipoproteins in a polarity-dependent manner in healthy men. Nutrition Research. Oct. 2013 [accepted manuscript]
• Small DM, Green BG. A proposed model of a flavor modality. In: Murray MM, Wallace MT, eds. The neural bases of multisensory processes. Boca Raton, FL: 2012
• Yokum S, Ng J, Stice E. Attentional bias to food images associated with elevated weight and future weight gain: an FMRI study. Obesity (Silver Spring) 2011;19:1775–83.

Choline Maximizes Carnitine Retention & Effects. Together, These Supplements May Promote Fat Loss + Lean Mass Gains and Boost Both Metabolic & Brain Health

The more choline the better the carnitine retention; and the better the retention the less high carnitine red mead you'll have to eat ;-)

If you are one of the many people who frequent boydbuilding-oriented bulletin boards, it is likely that you will have heard about the beneficial effects of exogenous insulin on the tissue storage of supplemental l-carnitine. When you hear something like this, or, as in this case, read about it in a forum, you can easily get the impression that it's only a matter of how much insulin you inject to turn an ergogenic aid, of which the majority of the scientific papers say that it is of questionable value, into a fat burning high performance powerhouse.

If said bulletin boards are not the only thing you frequent, i.e. if you are a regular at the SuppVersity, as well, you will probably also be aware of the fact that I strongly discourage the use of insulin in non-diabetic individuals - especially in cases as the one at hand, where it appears as if there were non-pharmacological alternatives to achieve increases in carnitine retention.

Using choline instead of insulin to maximize carnitine retention

I guess I could start this paragraph by stating that "it is a wonder that nobody appears to know about the interactions between choline and carnitine", but honestly, I have long given up to wonder when the respective information has to be looked up in studies that are older than 2-3 years. Studies as the one by Dodson and Sachan that was conducted at the University of Tennessee in the mid 1990 and the results of which werr published in the American Journal of Clinical Nutrition in 1996.

In the corresponding paper, Dodson and Sachan report the results of two experiments that were conducted to determine the effects of supplementary choline and/or pantothenate on the carnitine and lipid status of free-living humans:

Carnitine as Repartitioning Agent? + 7% Improvement in Lean- to Total Mass Ratio W/ HED of 1-1.5 of Carnitine/Day | more

"In experiment 1, adults receiving 13.5 mmol choline plus 1.4 mmol pantothenate/d had a significant decline in urinary carnitine excretion and renal clearance with nonesterfied carnitine (NEC) declining the most dramatically, 84%.

Additionally, serum NEC and total carnitine concentrations decreased significantly. No changes were observed in any of the serum lipids examined." (Dodson. 1996)

In the follow up experiment, Dodson and Sachan were able to show that the beneficial effects choline had on the retention of supplemental carnitine were not influenced by the provision of panthothenate, which had previously been used as a complement to carnitine and choline in clinical trials for a variety of neurologic and hyperlipidemic conditions.

Choline doesn't work for supplemental carnitine, only

Most of you will know that carnitine is not just a supplement, but also a non-essential nutrient. As long as we consume large enough quantities of lysine and methionine, the building blocks our bodies use to produce carnitine "on demand" we don't really need supplemental and probably not even dietary carnitine sources to survive (Mitchell. Feb. 1978).

Table 1: Total carnitine content of various foods (Mitchell. 1978)

Did you know that l-carnitine has for quite some time been touted to be a vitamin? The name vitamin BT is actually still sometimes used to refer to beta-hydroxy-y-trimethylamino butyrate aka carnitine; and that despite the fact that it can synthesized endogenously in mammals. It is thus not surprising that most carnitine-rich foods are animal products (see Table 1).

In view of our ability to produce "all the carnitine we need", it's actually not surprising that a sedentary slough is not going to benefit from respective supplements. And still, I had my reasonst to put the "all the canritine we need" in quotation marks. There are in fact situations, where research suggests that a lack of carnitine can become the bottle neck to fatty acid oxidization. The interesting thing about choline is now that it does not make a difference between endogenous and exogenous carnitine: Both are retained more effectively with an adequate / increased choline supply (Tsai. 1974, 1975; Carter. 1978; Hoppel). Low choline intakes, on the other hand, have been found to increase the urinary carnitine concentration and deplete the tissue stores independent of the overall nutritional status of the lab animals (Sheard. 1994).

In other words, the equation "higher choline = better carnitine levels" is valid irrespective of whether you are supplementing with beta-hydroxy-y-trimethylamino butyrate or simply producing it yourself.

SuppVersity Suggested Read: "Carnitine Loading Revisited: 3g Carnitine per Day Ward Off Vitargo Induced Fat Gain by Increasing Fatty Acid Oxidation and Total Energy Expenditure in 12 Week Human Study" | read more

Apropos nutritional status: I guess it's worth mentioning that fasting has been shown to lead to an increased mobilization of carnitine in order to facilitate the necessary increase of the carnitine-driven influx of fatty acids into the mitochondria in the absence of which the lean and obese subjects in a 1980 study by Hoppel et al. would have been starving.

Against that background it does not come as a surprise that the carnitine demands increase, when you go on a low carb or even ketogenic diet. In fact, Balaban-Gil et al. mention diet-induced carnitine deficiency as a potentially hepatoxic (=liver-damaging) side effect of long(er)-term ketogenic dieting (Balaban-Gil. 1998). They do yet also point out that the beginning liver damage can be sent into remission by the timely provision of supplemental l-carnitine.

On a side note: You do remember having read about the beneficial effects choline has on liver, did you? If not, I'd suggest you review my previous article "Choline: Stronger, Faster, Leaner & More Muscular, or Just Another Dumb-and-Barbell Story?" | read more.

More than just a life-insurance for the livers of keto dieters

As a diligent SuppVersity reader you will probably already know that choline, which used to be a staple supplement in the earlier days of bodybuilding, is a potent synergist to caffeine and carnitine - so potent in fact that I already devoted a whole post to the fat burning magic of the "CCC Stack" (read more).

Suggested Read:"Forgotten Dieting Aids: Choline, Carnitine, Caffeine and the Anti-Weight-Loss Plateau Effects of Sugar and Phosphates" | learn more

It would be pointless to repeat the discussion of the results of the 2003 study by Hongu and Sachan, so I'd suggest you (re-)read the corresponding article from February 2012, if you are interested how this combination lead to effortless weight loss in 19 healthy non-obese women.

I'd rather take a parting look at what actually happens to the carnitine in the Dodson and Sachan study. It was neither excreted nor pooling up in the blood of the 29 healthy volunteers when they consumed 13.5mmol of choline (ca. 1.4g of choline) as choline bitartrate (~3g) for 7 days and choline + of carnitine for additional three days.

Due to the fact that Dodson and Sachan who have been working at the University of Tennessee, back in the day, did not conduct muscle, let alone heart, brain, kidney and liver biopsies. We will (unfortunately) have to content ourselves with the results of a 1998 guinea pig  study from the same work group (Daily. 1998), if we want to understand the fate of the "missing" carnitine.

Total ingested (full bars) and absorbed (blue part of the bar) amount of dietary carnitine in mg/kg body weight (from Amino Acids for Super Humans)

When and how do you take carnitine and choline? If we put some faith into the non-published data from previous experiments by Dodson & Sachan, the responses should identical irrespective of whether you take the supps at one time or in several doses throughout the day. If we do now take the study by Hongu and Sachan as a guide the "recommended dosage" would amount to ~3g of choline bitartrate + 1.4g of carnitine - in view of the fact that Hongu's & Sachan's subject were women maybe up to 4g choline + 2g of carnitine per day for the heavier guys out there.

I know an animal model is not ideal, but it's better than trying to guess what caused the slight decline in serum levels and significantly lower urinary losses in the human trial from 1996 (Dodson. 1996); and the interaction of choline and carnitine in guinea pigs is more akin to humans than that of rodents, which is, according to Daily et al. (1998), probably a direct consequence of a lower choline oxidase activity in Guinea pigs vs. rats / mice.

What exactly happens to the carnitine, when you consume extra choline?

The study protocol Daily et al. used was slightly different from the one Dodson and Sachan had used in their 1996 human trial: Instead of carnitine and choline, the guinea pigs received only choline (+200% more than the regular diet would offer).

Figure 1: Changes in carnitine content of brain, liver, heart, kindney and muscle (left) and differences in body composition (right) extra choline vs. normal chow (Daily. 1998)

As you can see in Figure 1, there was a significant reduction in kidney carnitine (remember that this is where the carnitine is extreted) and concomittant increases in brain (specifically acetyl-carnitines) and muscle carnitine (total carnitine) content. The levels in the livers and hearts of the guinea pigs, on the other hand, remained stable (p > 0.05).

The question whether these changes were the cause or just correlates to the beneficial effects the provision of additional choline had on the body composition (see Figure 1, right) of the hairy mini remains to be answered, though. On the other hand, it is quite certain that the observations Daily et al. made in their lab animals stand in line with the results of Hongu et al.'s human trial from 2003, which clearly suggests that the "selective accretion of nitrogen and depletion of fat", of which Daily et al. state that it is an "important and unique consequence of choline–carnitine interactions" is not species dependent and occurs even in the absence of caffeine, the CNS stimulant Hongu et al. added to the equation.

Is choline the missing link, or rather the missing synergist due to which most of the studies that investigated the ergogenic effects of l-carnitine yielded very disappointing results?

In view of the fact that reviews as the one by Bass regularly refer to the fact that "muscle carnitine content is not easily increased with carnitine supplementation" (Brass. 2004) as one of the underlying reasons for the disappointing results that have been reported in a whole host of studies, it appears not too far-fetched to hypothesize that some of the trials may have yielded very different results if the researchers had used a combination of carnitine and choline.

Speaking of the synergy of choline + carnitine: You probably remember the study that claimed to show that the "high" carnitine content of red meat was carcinogenic, right? I have discussed the fallacy of this assumption in a separate article (read more) and I am not really interested to revive this discussion, that the moment.

What I am interested in, though, is red meat or rather the fact that the major carnitine sources in our diet, i.e. animal products, always come with choline. For beef, for example, the ratio is almost 1:1 (depending on the reference you use). At this point I could probably say something about "nature knows" best. That would be an understatement, though. If we are honest with ourselves, it's after all more like "nature knows" and "we are groping in the dark" - wouldn't you agree?

Bottom line summary: Before I summarize what you could have learned today if you actually read the article, I briefly want to remind you of the general health & performance benefits of choline I wrote about before (read more). After reading today's article you can thus expand the said list or your own mental notes about the useful effects of choline by the following items::

• The provision of choline reduces the high urinary excretion of carnitine which has always been the bottleneck of carnitine supplementation.
• In human studies, the combination of choline + carnitine + caffeine has been shown to promote fat loss. If we take the corresponding study as a reference, an effective dosing regimen would contain ~3g of choline bitartrate + 1.4g of carnitine.
• From animal trials we know that the changes in body composition are accompanied by significant increases skeletal muscle and brain total and acyl-carnitine levels. In view of the physiological role carnitine plays in the oxidation of fatty acids in the mitochondria, it is likely that the increase in muscular carnitine levels is mechanistically involved in the repartitioning effects (increased muscle decreased fat mass).
• The increased mobilization and clearance of carnitine in the fasted state suggest that choline and carnitine will be most useful, when you are dieting - in  this case even in the absence of additional caffeine, which is otherwise needed to increase the serum levels of readily oxidizable free fatty acids.
• Case reports from children on ketogenic diets suggest that l-carnitine supplementation can become mandatory to avoid liver damage, when patients are in full ketosis for a long period of time. Even in the absence of specific trials, it is thus reasonable to assume that a combination of l-carnitine and choline should have beneficial effects for anyone following a ketogenic or very low carb diet.

One last note: If you take a look at the interaction between choline and carnitine and the role carnitine plays in liver (=help oxidize fatty acids before they start clogging the liver → NAFLD), brain (=improve + maintain cellular energy status & neuronal function) and muscle (=improve fatty acid oxidation), it cannot be excluded that many of the previously listed health & perfomance effects of choline are actually mediated by its interaction with endogenous carnitine.

References:

• Ballaban-Gil K, Callahan C, O'Dell C, Pappo M, Moshé S, Shinnar S. Complications of the ketogenic diet. Epilepsia. 1998 Jul;39(7):744-8.
• Brass EP. Carnitine and sports medicine: use or abuse? Ann N Y Acad Sci. 2004 Nov;1033:67-78. Review.
• Carter AL, Frenkel R. The relationship of choline and carnitine in the choline deficient rat. J Nutr l978;108:l748-54.
• Daily JW III, Hongu N, Mynatt RL, Sachan DS.  Choline supplementation increases tissue concentrations of carnitine and lowers body fat in guinea pigs. The Journal of Nutritional Biochemistry. 1998; 9(8): 464–470.
• Dodson WL, Sachan DS. Choline supplementation reduces urinary carnitine excretion in humans. Am J Clin Nutr. 1996 Jun;63(6):904-10. 
• Hongu N, Sachan DS. Caffeine, carnitine and choline supplementation of rats decreases body fat and serum leptin concentration as does exercise. J Nutr. 2000 Feb;130(2):152-7.
• Hongu N, Sachan DS. Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. J Nutr. 2003 Jan;133(1):84-9.
• Hoppel CL, Genuth SM. Carnitine metabolism in normal-weight and obese human subjects during fasting. Am J Physiol. 1980 May;238(5):E409-15.
• Mitchell ME. Carnitine metabolism in human subjects. I. Normal metabolism. Am J Clin Nutr. 1978 Feb;31(2):293-306. Review.
• Mitchell ME. Carnitine metabolism in human subjects. II. Values of carnitine in biological fluids and tissues of "normal" subjects. Am J Clin Nutr. 1978 Mar;31(3):481-91. Review.
• Sheard NF, Krasin B. Restricting food intake does not exacerbate the effects of a choline-deficient diet on tissue carnitine concentrations in rats. J Nutr. 1994 May;124(5):738-43.
• Tsai AC, Romsos DR. Leveille GA. Significance of dietary carnitine for growth and carnitine turnover in rats. J Nutr l974;104:782-92.
• Tsai AC, Romsos DR. Leveille GA. Determination of carnitine turn over in choline-deficient and cold-exposed rats. J Nutr 1975;105: 301-7. 

Phenibut, Addictive Sleep Aid With Unhealthy Hangover? Dosages, Effects, Side Effects and Safety Concerns

Some say phenibut has addictive potential, others say it stops working after only a week and a third group of people will tell you that it's highly toxic and should not be used anyway... What's true? What's bogus? And how likely is it that phenibut helps / hurts you?

In a way today's SuppVersity article is part of the reverberations of the last installment of the Science Round Up, where Carl and I have been talking about the non-existent or surprisingly excitatory effects of GABA in certain individuals. I also presented a list of GABA alternatives that ranged from valerian to melatonin - a list of natural alternatives which did for that very reason not include phenibut (also "phenybut"; I will refer to it as "PB" for convenience reasons), a γ-aminobutyric acid (GABA) molecule with an additional phenyl group in the β-position.

It is this small, but important structural difference that allows the phenibut molecules to pass through the blood brain barrier (Shulgina. 1989) and allows them to do everything GABA should, but oftentimes cannot do, because it does not reach its destination in the brain.

What effects are we talking about here? 

According to Lapin phenibut can relieve tension, anxiety, and fear, and improve the sleep quality - specifically in psychosomatic or neurotic patients (Lapin. 2001). It is however important to remember that the effects are dose- and in some cases also patient-specific. Systemically administered phenibut produces a great variety of central effects:

• At doses that do not affect motor activity (e.g., 20 mg /kg; HED 1.6mg/kg) PB inhibits food conditioned reflexes in mice. 
• At doses higher than 70 mg kg i.p. (HED 5.7mg/kg) PB reduces motor and exploratory activities, rearings, muscle tone, coordination and body temperature.

Moroever, PB has been shown to potentiates the central effects of the anesthetics ether, chloral hydrate, and barbiturates - so you better be careful with PB supplements if you are scheduled to be exposed to any of those.

PB does not take much for the nootropic effects

In contrast to its anxiolytic and narcotic effects, PB's nootropic effects have been observed in rodent models at dosages as low as 5 to 10 mg/kg. In human beings this would equal ~0.4-0.8mg/kg and thus less than 75mg for the vast majority of us. Interestingly, ...

Table 1: Pharmacological effect of phenibut, diazepam, and piracetam based (Lapin. 2001)

"[t]he anxiolytic effect of PB appears to be dependent on the emotional reactivity of the animals. In anxious and passive cats, PB abolished or suppressed fear and brought about an aggressive reaction to provocation. In aggressive cats PB had no effect on aggression. In non-aggressive cats without obvious fear, PB expanded the scope of positive emotional symptoms." (Lapin. 2001)

In view of the fact that similar observations have been made in rabbits by Zyablitseva et al. in 2008, we may - not without the necessary healthy skepticism, though - assume that a similar influence of the baseline mental state can be observed in human beings, as well. This would imply that the often described calming effects will be most pronounced in those of us who are already chillin'. To effectively blunt aggression, on the other hand, dosages in the 2g+ range would be necessary (estimate based on rodent studies) and I hope I don't have to warn you that this amount of PB will leave you paralyzed if not worse!

GABA & dopamine, the phenibut double-whammy

Despite the fact that the majority of its effects are probably mediated by the interaction between the PB molecules and the GABA receptors, the existing research, the majority of which happens to be in Russian, suggests that PB may also stimulate dopaminergic processes and that this effect may be important for the sedative and tranquilizing effects of the drug (Goldblat. 1986; Mehilane. 1990).

Warning: Compounding phenibut with succinate, malate, nicotinate or glutamic acid can modify not just the potency, but also the expressiveness of some particular effects (Tiurenkov. 2011). These PB + organic acid combinations are thus not necessarily save and their effects are difficult to predict - you better stay away!

The antagonistim between PB and PEA (β-phenethylamine), on the other hand, could explain the anxiolytic (=anti-anxiety) effects of this compound, of which you should by now have realized that it PB is somewhat of a diva.

If the timing and dosing are right, it does however have some pretty interesting effect that do in fact reach far beyond the psychological effects that come with the changes in neurotransmitter levels.

• This is what WebMD will tell you about the current usage (of phenibut) - "Used for: Anxiety. Alcoholism. Irregular heartbeat. Fear. Insomnia. Tension. Stress. Fatigue. Post-traumatic stress disorder (PTSD). Depression. Improving memory, learning, and thinking. Other conditions."
  Researchers from the Volgograd State Medical Academy, for example, report that the use of PB can help ameliorate stress induced overload of the heart (Perfilova. 2007), protect the heart against the damaging effects of alcoholism (Perfilova. 2006).
• In a similar vein phenibut has been shown to protect against the phsychological side effects of chronic stress. In rodent models, it reduced the intensity of emotional disorders in the open-field test and elevated plus maze test, ameliorated cognitive disorders in the tests for conditioned avoidance response and extrapolatory deliverance and limited stress reaction due to a decrease in the intensity of adrenal hypertrophy, thymus involution, and stomach mucous membrane ulceration (Tiurenkov. 2012).

Moroever, data from 2011 suggests that phenibut (at a relatively high HED of 325mg) and other GABA-ergic agents can protect against lipopolysacharide(LPS)-induced immune stress as it would be produced by a leaky gut (Samotrueva. 2011) 

There is still one problem: Rumors have it phenibut is not save!

Let's be honest, what would the best nootropic, tranquilizing, sleep booster be worth, if using it would pose a serious health risk? How serious? Well about as serious as this:

• 

  In case I am not around, when you read the results of study, it may come handy to be able to calculate the human equivalent doses for mice, rats, rabbits, pigs and other animals, wouldn't it? If you'd agree I'd suggest you head over and read my previous article on "Human Equivalent Dosages" | read more

  PB has relatively a low lethal dose 50 of 900mg/kg in mice (HED: 73mg/kg) and 700mg/kg in rats (HED: 113mg/kg; the LD50 is the amount of a substance that has to be administered so that 50% of the lab animals die). It should be said, though, that I do have a case report here informing me that a former drug addict went up to 20g per day (Högberg. 2013), when he noticed that his new "dope" lost its efficiacy after only one week and survived - not without a serious psychosis, though!
  
• PB has some addictive potential. The previously case report of the drug addict makes it quite clear: For susceptible individuals the tranquilizing effect of PB will definitely have addictive potential (Samokhvalov. 2013). Plus, the fact that it loses its effect pretty rapidly is not going to help to stay within the "no danger zone", either

Ok, I know what you are thinking now: "Where is the rest of the side effects, the addictions and the psychoses?" And yes, that's basically what I have been asking myself as well, when I started searching for studies to confirm the horror stories you hear about phenibut on the Internet. A single ex-substance-abuser who overdoses on 20g(!) of phenibut is not exactly what I was thinking of, when I started researching the often-touted health hazards of an OTC supplement, of which the next best user report on reddit will tell you that "after 7 days on 4 grams/day" the corresponding user became "addicted" and "decided to go cold turkey" (google it up, if you want the source). The purported results of not following any of the Three Simple Rules of Sensible Supplementation were:

"[L]iterally no sleep, not being able to eat anything, severe depression/serious contemplation of suicide, loud tinnitus, pissing/shitting(barely anything) every 30 minutes and overall mild body pain" (I will leave it with "Anonymous")

If we look at the results of the rodent studies 2,000g/d would equal a rodent dosage of ~300mg/kg which is, as you probably realize, already 1/3 of the dosage that will kill (!) more than 50 in 100 mice who received a 300mg/kg dose of phenibut via intraperitoneal injection (~orally; the injection is used to avoid that the animals regurgitate the drugs, the pharmacology is however similar to regular oral consumption).

So if 20g is insane and 2g already too much how much would be sane? As much as I would like to provide you with a scientifically verified dosing recommendation, I can't. The necessary evidence from human studies is simply non-existent and even if it was, it would probably be suspect to high inter-individual variability and vary from one desired outcome to another. What I can tell you, though is this:

• 

  Listen to the Science Round-Up and read the corresponding article to learn more about GABA and potential PB alternatives | go ahead!

  Based on rodent studies, you should feel nootropic effects with dosages as low as 75mg.
• Based on what I read on "the boards", dosages in the 125-500mg range appear to produce relaxation effects that help you sleep.
• Moreover, common sense tells you that the (allegedly) inevitable "phenibut resistance" will occur faster with higher dosages, therefore it appears reasonable to soft-paddle and cycle β-Phenyl-GABA (PB).

In view of the non-existent scientific evidence with regards to its long-term safety, I would strongly caution against taking it each and every night. The mere fact that there is an accommodation effect and that PB holds the potential for dose-depended withdrawal symptoms should tell you that it messes with the neurotransmitter levels in your brain and that's nothing you would want to risk, if practicing sleep hygiene, stress reduction and - if all that does not help - the use of safer alternatives should actually suffice to alleviate your sleep problems. Used irregularly and as a "quick fix", it is however unlikely to be "worse" than the average FDA regulated sleeping pill.

References:

• Danilin VP, Krylov EN, Magalif AIu, Rait ML. [Effect of fenibut on the nocturnal sleep of patients with the alcoholic abstinence syndrome]. Zh Nevropatol Psikhiatr Im S S Korsakova. 1986;86(2):251-4. 
• Goldblat YuV, Lapin IP. Potentiation of the therapeutic effect of antiparkinsonian drugs by phenibut.Zh Nevropatol Psikhiatrii1986;86:1146–1148 (in Russian with English summary).
• Högberg L, Szabó I, Ruusa J. [Phenibut yielded withdrawal symptoms and psychosis. Drugs for cosmonauts--now marketed as dietary supplements online]. Lakartidningen. 2013 Apr 17-23;110(16):825-7. 
• Tiurenkov IN, Bagmetova VV, Krivitskaia AN, Berestovitskaia VM, Vasil'eva OS. [Psychotropic effect of phenibut salts and their compositions with organic acids]. Eksp Klin Farmakol. 2011;74(2):3-7.
• Lapin I. Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug. CNS Drug Rev. 2001 Winter;7(4):471-81.
• Samotrueva MA, Magomedov MM, Khlebtsova EB, Tiurenkov IN. [Influence of GABA derivatives on some indices of lipid peroxidation in immunocompetent organs under experimental immunopathology conditions]. Eksp Klin Farmakol. 2011;74(8):32-6.
• Mehilane LS, Rago LK, Allikmets LH.Pharmacology and clinic of phenibut.Tartu: Izd. TGU, 1990 (in Russian with English summary). 
• Perfilova VN, Tiurenkov IN, Berestovitskaia VM, Vasil'eva OS. [Cardioprotective effect of GABA derivatives in acute alcohol intoxication]. Eksp Klin Farmakol. 2006 Jul-Aug;69(4):23-7.
• Perfilova VN, Tyurenkov IN, Lebedeva SA, Volotova EV, Berestovitskaya VM, Vasil'eva OS. Effect of citrocard on functional reserves of the heart under conditions of chronic stress. Bull Exp Biol Med. 2007 Jul;144(1):21-5.
• Shulgina GI. On neurotransmitter mechanisms of reinforcement and internal inhibition. Pavlov J Biol Sci. 1986 Oct-Dec;21(4):129-40.
• Tiurenkov IN, Bagmetova VV, Borodkina LE, Berestovitskaia VM, Vasil'eva OS. [Fenibut and its citrate prevent psychoneurological disorders caused by chronic stress (paradoxical sleep deprivation)]. Eksp Klin Farmakol. 2012;75(6):8-13.
• Zyablitseva EA, Pavlova IV. Effects of the GABA receptor agonist phenibut on behavior and respiration in rabbits in emotionally negative situations. Neurosci Behav Physiol. 2008 Jul;38(6):555-62.

Ingestion of 400mg Caffeine Before a Workout Can Prevent Delayed Onset Muscle Soreness in Resistance Trained Men

Too many side-laterals without coffee?

Still having DOMS despite Alex Leaf's article on "DOMS - Delayed Onset Muscle Soreness: What Is DOMS & How Can It Be Managed? Science, Strategies, Supplements" (read more)?

In that case you are probably not a great fan of pre-workout products, coffee or energy drinks, because if you were, it is not unlikely that you had - instinctively, if you will - done everything right by consuming a hefty dose of the world's #1 OTC drug, caffeine, before each of your workouts.

400mg is plenty, but it does the trick

In case you have no clue what I am talking about, I'd suggest you take a look at the results of a recent paper by Hurley, Hatfield, and Riebe in the Journal of Strength and Conditioning Research (Hurley. 2013). In a series of tests that involved a strenuous biceps workout 4 sets of 10 bicep curls on a preacher bench, followed by a fifth set in which subjects completed as many repetitions as possible. The workout that was performed twice, with a one-week "wash-out" period - once with and once without the ingestion of 5mg/kg of caffeine 1h before the training session.

When the scientists compared the performance, perceived exertion and post-workout muscle soreness parameters they found that the ingestion of 5mg/kg caffeine ...

• had a beneficial effects on the perception of muscle soreness, 
• reduced the levels of perceived exertion, and
• lead to significant increases in performance

As you can see in Figure 1 the equivalent of ~2-3 cups of coffee did nut just ameliorate the pain on day 2 after the workout (that's usually when DOMS hits you hard). It did also speed up the "regeneration", or rather the reduction of pain.

Figure 1: Soreness values expressed relative to baseline testing (left) CK levels after the training session and number of repetitions on the all-out set (right; Hurley. 2013)

I have to admit, I was tempted to write that caffeine sped up the recovery process, but if you read part II of Alex' two-part series on DOMS, you will be aware that it is not warranted to use DOMS as a marker of regeneration ("DOMS - Delayed Onset Muscle Soreness: No Pain, No Gain? Is DOMS Necessary to Build Muscle?" | learn more).

The repeated bout effect is the opposite of the anabolic resistance that can occur after weeks of training | learn more

What about the repeated bout effect? What if it skewed the results? The increase in performance and reduce in muscle damage upon the exposure to a "conditioned" stimulus could in fact have led to lower DOMS values in the second of the two testing session. Hurley et al. do however point out that this effect would be minized by counterbalancing and appropriate randomization as it was conducted in the study at hand.

The non-existent effects on the creatine kinase (CK) levels of the the 12 healthy resistance-trained men (age 18–25 years) supports Alex' assessment that the link between CK and DOMS is a temporary one: While the peak values of DOMS and CK occur at the same time, a high CK level does neither predict a high degree of delayed onset muscle soreness, nor vice versa.

So what's the mechanism here

In view of the fact that the continuous provision of caffeine throughout the recovery phase did not lead to similar / increased reduction in DOMS, it appears certain that the effects of caffeine are acute. This means it works only, if it is ingested 1h before the workout and will thus achieve it's peak value when you are actually working out (depending on the dosage and delivery method, the caffeine levels peak after 40-60 min).

As Hurley et al. point out, the effect could be brought about by a partial blockade of the natural increase in muscular adenosine concentrations that have been observed to increase in the working muscle and blood after high-intensity exercise in previous studies (Tarnopolsky, 2000; Davis. 2003; Motl. 2006). It would also stand in line with the (unsurprising) observation that the subjects’ perceived exertion was significantly lower with caffeine in the final 3 sets of exercise - an effect that has also been attributed to the adenosine-inhibiting effects of caffeine (Davis. 2003):

"This response is attributed to the role of caffeine as a CNS stimulant and inhibiting adenosine receptor activity. Caffeine stimulates the CNS by secreting serotonin into the cerebral cortex, which results in mood improvements, increased mental awareness, and decreased fatigue and tiredness. This is all a result of inhibited adenosine activity thus reducing perception of pain, which could increase ability to perform more repetitions." (Hurley. 2013)

In view of the fact that the adenosine levels have not been accessed, the authors are eventually still stuck for an answer with respect to the exact underlying mechanism of the anti-DOMS effects of caffeine. Adenosine is a likely candidate, though, and before I would do a follow up study on this, I would rather take some money to find out whether 400mg of caffeine taken before a PM workout won't be doing more harm than good by having profound negative effect on your sleep quality.

Sometimes the things we learn from scientific studies have questionable, limited or no practical relevance. For others, like the study at hand or a previous study on the "muscle shaping effects" of certain exercises, this is luckily not the case (read more)

"Who cares about mechanisms, if it works?" I guess in view of the many in-vitro studies we are being bombarded with on a daily basis, most of you will probably agree that not knowing the exact mechanism of the DOMS-reducing effects of 5mg/kg of coffee is less problematic than knowing about the mechanism by which a certain substance works, but being clueless whether and at which doses it will produce the desired effects in humans - right?

Right! Unfortunately, even the results of the study at hand come with a small "*" [asterisk] to indicate that the benefits were observed in subjects who consumed coffee and caffeinated beverages only occasionally. Based on the observation that the performance enhancing effects of caffeine do not differ between habitual / non.habitual caffeine consumers (Tarnopolsky. 2000; Astorino. 2007), it does however appear likely that this is not going to be an issue.

References:

• Astorino TA, Rohmann RL, Firth K, Kelly S. Caffeine-induced changes in cardiovascular function during resistance training. Int J Sport Nutr Exerc Metab. 2007 Oct;17(5):468-77.
• Davis JM, Zhao Z, Stock HS, Mehl KA, Buggy J, Hand GA. Central nervous system effects of caffeine and adenosine on fatigue. Am J Physiol Regul Integr Comp Physiol. 2003 Feb;284(2):R399-404. Epub 2002 Oct 24.
• Hurley CF, Hatfield DL, Riebe DA. The effect of caffeine ingestion on delayed onset muscle soreness. J Strength Cond Res. 2013 Nov;27(11):3101-9.
• Motl RW, O'connor PJ, Tubandt L, Puetz T, Ely MR. Effect of caffeine on leg muscle pain during cycling exercise among females. Med Sci Sports Exerc. 2006 Mar;38(3):598-604.
• Tarnopolsky M, Cupido C. Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers. J Appl Physiol (1985). 2000 Nov;89(5):1719-24.